1. Field of the Invention
The present invention is directed to novel dopamine transporter imaging ligands that exhibit high selectivity for dopamine transport combined with a rapid apparent equilibrium of striatal-to-cerebellar ratios.
2. Discussion of the Related Art
Since the initial preparation by Clarke and co-workers over twenty-three years ago, (Clarke et al, J. Med. Chem., 16, 1260-1267 1973), the 3xcex2-(substituted phenyl)tropane-2xcex2-carboxylic acid methyl ester class of compounds has been widely employed in structure-activity relationship (SAR) studies at the cocaine binding site on the dopamine transporter (DAT).
The 3xcex2 (substituted phenyl)tropane-2xcex2-carboxylic acid esters are effective in vivo binding ligands for dopamine transporters (DATS) (Scheffel and Kuhar, Synapse 4:390-392, 1989; Boja et al., Dopamine Receptors and Transporters, 611-694, Marcel Dekker, Inc., 1994). For example, RTI-55, a member of this class, has been used in many studies in animals and humans as a Positron Emission Tomography (PET) or SPECT (single photon emission computed tomography) ligand (Boja et al., Ann. N.Y. Acad. of Sci. 654:282-291, 1992, and Boja et al., 1994). Highly desirable properties of a DAT ligand include rapid penetration into the brain, achievement of rapid apparent equilibrium, and high signal to noise ratios. Various 3xcex2-phenyltropane analogs and other compounds possess these properties to varying degrees.
The 3xcex1 isomer of RTI-55, RTI-352, is an effective in vivo binding ligand that reflects greater selectivity for the dopamine transporter than is observed with RTI-55. In addition, there is also a more rapid achievement of apparent equilibrium in the striatal-to-cerebellar ratio (compared to RTI-55) as the ratio peaks at about 30 min and is maintained for about 20 min thereafter. Such apparent equilibrium is useful in developing an approach to measuring the number of dopamine transporters present in tissues. Moreover, these results indicate that the utilization of 3xcex1 isomers of a variety of 3xcex2-(substituted phenyl)tropanes will result in greater selectivity for dopamine transporters and a more rapid achievement of apparent equilibrium.